A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations, resulting in numerous publications in the past. We have recently published results of a genome-wide association study (GWAS) of refractive error in the AREDS, KORA, Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia, with confirmation of the discoveries from these data in several other GWAS. During this year we have published similar analyses of myopia and hyperopia (1) and bipolar disorder (using the AREDs data as controls in a collaborative study) (2). Whole exome SNP array genotyping was performed in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We are analyzing these data using multiple approaches to detect rare variants that contribute to refractive error traits. This year we have published results from one of these datasets (3) evaluating ancestry and risk factors for age-related macular degeneration in a population isolate. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2. The collaborative analyses performed by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. Previously, we performed analyses on our AREDS, KORA and FES GWAS data for meta-analyses of refractive error by the CREAM consortium and were co-authors on multiple papers presenting these results. Dr. Bailey-Wilson is co-leading the CREAM study of astigmatism with Dr. Jeremy Guggenheim and our first astigmatism meta-analysis was published this year (4). We have also completed analyses of myopia on the AREDS data for the next CREAM meta-analysis and are also leading a second astigmatism meta-analysis. We have begun a new project with CREAM, whereby our group will recall all genotypes jointly across studies in CREAM that used the same Illumina Exome-chip genotyping platforms. This is expected to improve the quality of all the genotype calls for rare variants and will make a major contribution to all of the planned CREAM meta-analyses of exome-chip data. We have also contributed results from the FES study to a meta-analysis of intraocular pressure that was published this year (5). Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic and Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on studies of oral clefts. We have recently performed a study attempting to identify gene-gene interactions within the WNT pathway for nonsyndromic oral clefts (with or without cleft palate) using Asian and European trio data. This project used some methods newly developed by our group as part of another Annual Report and was published this year (6). We are currently analyzing whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees and a manuscript is under development. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for excess hypocholesterolemia in autistic individuals has been observed in some multiplex families Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. Whole exome sequence data for all of the families is now being analyzed. Since the data were sequenced over a long time period, we are recalling all the data together and analyses will be ongoing over the next year. We are also collaborating with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to analyze WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. All of these data have now been sequenced and analyses are underway. Utilizing the sequence data from this project as controls (along with othet datasets) we published a paper this year that estimated the frequency of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1 (7). Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage analyses have been completed in these families. Dr. Bailey-Wilson was awarded WES sequencing of these families through a competitive application to the National Intramural Sequencing Center (NISC) and WES analyses have just been completed in all of our families. Analyses of these data are ongoing, using methods available in Golden Helix SVS as well as methods developed in Dr. Bailey-Wilsons Section under another Annual Report. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study of healthy young adults. This work is ongoing; several papers are in preparation or under review. A paper presenting evidence of genetic variants that influence circulating pyridoxal 5-phosphate concentration was published this year (8). Dr. Claire Simpson, a Staff Scientist, and Dr. Bashira Charles, a Research Fellow, have continued their collaboration with Dr. Steve Brant of Johns Hopkins School of Medicine. They are analyzing GWAS data on 500 African American Crohn's Disease patients. Dr. Simpson has completed linkage analyses on 12 members of a Jewish Crohn's Disease pedigree and follow-up is ongling. She and Dr. Brant plan to perform exome sequencing, DNA methylation and RNASeq expression analysis in affected sib pairs from his collection of Jewish families with Crohn's Disease. Drs. Simpson and Charles are currenlty working on GWAS and admixture studies. Dr. Simpson was a coauthor this year on a paper characterizing genetic loci that affect risk of IBD in African-Americans (9). Dr. Simpson was also first author of a study of barriers and ethical challenges in genetic data sharing that was published this year, based on a questionnaire survey of members of the International Genetic Epidemiology Society (10). Dr. Simpson has also established a collaboration (independent of Dr. Bailey-Wilson) with Dr. Rebecca Schmidt, Dr. Kyoungmi Kim and Dr. Irva Hertz-Picciotto at UC Davis (ENIGMA - Exploring Nutrient Interactions with Genetics as Mechanisms for Autism Spectrum Disorder) to examine gene-environment interactions in their MARBLES and CHARGE studies. This work will study the interaction between nutrition and genetics in ASD etiology. All analyses will use previously measured genotype data from the Affymetrix population specific EUR array on approximately 1000 CHARGE children, 497 with ASD and 553 typically developing. All data cleaning is now complete and analyses are ongoing. Dr. Emily Holzinger this year published work that was an extension of her PhD studies, showing that genetic variation in iron metabolism is associated with neuropathic pain in HIV-infected patients (11). She has also continued working on a manuscript from her PhD work in which she developed a computationally efficient data analysis pipeline for identifying genetic interactions associated with quantitative lipid traits; this manuscript is currently under review.